Regulating Interactions Between Targeted Nanocarriers and Mononuclear Phagocyte System via an Esomeprazole-Based Preconditioning Strategy

Abstract

Zakia Belhadj,1 Bing He,1 Jijun Fu,2 Hua Zhang,1 Xueqing Wang,1 Wenbing Dai,1 Qiang Zhang1 1Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, People’s Republic of China; 2School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, People’s Republic of ChinaCorrespondence: Qiang Zhang; Wenbing Dai Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery SystemsState Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, People’s Republic of ChinaTel [phone]; Tel [phone]Email [email protected]; [email protected]: The mononuclear phagocyte system (MPS) presents a formidable obstacle that hampers the delivery of various nanopreparations to tumors. Therefore, there is an urgent need to improve the off-MPS targeting ability of nanomedicines. In the present study, we present a novel preconditioning strategy to substantially increase the circulation times and tumor targeting of nanoparticles by regulating nanocarrier-MPS interactions.Methods: In vitro, the effect of different vacuolar H+-ATPase inhibitors on macrophage uptake of targeted or nontargeted lipid vesicles was evaluated. Specifically, the clinically approved proton-pump inhibitor esomeprazole (ESO) was selected as a preconditioning agent. Then, we further investigated the blocking effect of ESO on the macrophage endocytosis of nanocarriers. In vivo, ESO was first intravenously administered into A549-tumor-bearing nude mice, and 24 h later, the c(RGDm7)-modified vesicles co-loaded with doxorubicin and gefitinib were intravenously injected.Results: In vitro, ESO was found to reduce the interactions between macrophages and c(RGDm7)-modified vesicles by interfering with the latter’s lysosomal trafficking. Studies conducted in vivo confirmed that ESO pretreatment greatly decreased the liver and spleen distribution of the targeted vesicles, enhanced their tumor accumulation, and improved the therapeutic outcome of the drug-loaded nanomedicines.Conclusion: Our findings indicate that ESO can regulate the nanoparticle-MPS interaction, which provides a feasible option for enhancing the off-MPS targeting of nanomedicines.Keywords: mononuclear phagocyte system, preconditioning strategy, esomeprazole, V-ATPase inhibitors, targeted lipid vesicles

Keywords

• mononuclear phagocyte system
• preconditioning strategy
• esomeprazole
• v-atpase inhibitors
• targeted lipid vesicles